The growing need for the early diagnosis and assessment and/or treatment of diseases can potentially be addressed by pharmaceuticals that preferentially accumulate at the disease sites. In diagnostic applications, these pharmaceuticals can elucidate the state of the disease through its distinctive molecular biology expressed as disease markers that are not present, or are present in diminished levels, in healthy tissues. In therapeutic applications, these pharmaceuticals can deliver an enhanced dose of therapeutic agents to the disease sites through specific interactions with the disease markers. By specifically targeting physiological or cellular functions that are present only in disease states, these pharmaceuticals can report exclusively on the scope and progress of that disease or exclusively target the diseased tissue. A signal-generating or signal-enhancing moiety is a key element of these diagnostic pharmaceuticals, which produce differentiated signals at the disease sites. Such signals can be captured and processed to produce images of the tissue of interest. Many such signal-generating or signal-enhancing moieties comprise metals, which are often physiologically toxic in their uncombined forms. Therefore, these metals are often bound to chelators to form nontoxic complexes. The utility of such a diagnostic pharmaceutical is much enhanced if the metal is not easily dissociated from the chelator moiety before the complex reaches the disease site. Furthermore, such a diagnostic pharmaceutical should be provided with a moiety that targets the disease sites.
To date, a number of chelators have been used, including diethylenetriaminepentaacetic acid (“DTPA”); 1,4,7,10-tetraazacyclododecane′-N,N′N″,N′″-tetracetic acid (“DOTA”); and derivatives thereof. These chelators have acceptably high stability constants (also known as formation constants) with respect to gadolinium, and thus could act to detoxify gadolinium ions. However, the stability constant of a chelator with respect to useful metals or metal ions varies. Therefore, a continued need exists for chelators that have high stability constants with respect to many useful metals or metals ions that may be used in designing many diagnostic pharmaceuticals. It is also desirable to provide metal-chelator complexes that are readily conjugatable to molecules that can accumulate at disease sites.